Presentation and applied case study of a system-wide workflow which supports rapid, systematic and efficient continuous seeded cooling crystallisation process design, with the aim to deliver a robust, consistent process with tight control of particle attributes.

Using antisolvent crystallisation of salicylic acid as the model process, we report our experimental investigation into the temporal and spatial steady states of solution concentration and mean crystal size in a continuous oscillatory baffled crystallizer. The evolutions of the two parameters over time and distance along the crystallizer are measured for a variety of operating conditions. The results show that the attainment of long term temporal and spatial stabilities (>100 residence times) for the solute concentrations are easily achieved, whereas the temporal steady states of the mean crystal size are more difficult to accomplish, even though the spatial steady states have been obtained. A simplified population balance model is applied to the experimental data for the determination of nucleation and growth kinetic parameters. From which both the solution concentration and the mean size were predicted and matched to experimental values reasonably well. In addition, we have identified and executed the conditions of long term steady states for extended operation of 6.25h to produce close to 1kg of crystal product with minimal variation in crystal size (±3.01μm)

In this work, we outlined an experimental workflow enabling the rapid assessment of primary and secondary nucleation and crystal growth kinetics. We used small-scale experiments in agitated vials with in situ imaging for crystal counting and sizing to quantify nucleation and growth kinetics of α-glycine in aqueous solutions as a function of supersaturation at isothermal conditions. Seeded experiments were required to assess crystallization kinetics when primary nucleation is too slow, especially at lower supersaturations often encountered in continuous crystallization processes. At higher supersaturations, we compared results from seeded and unseeded experiments and carefully analyzed interdependencies of primary and secondary nucleation and growth kinetics. This approach allows for the rapid estimation of absolute values of primary and secondary nucleation and growth rates without relying on any specific assumptions about functional forms of corresponding rate expressions used for estimation approaches based on fitting population balance models. Quantitative relationships between nucleation and growth rates at given conditions provide useful insights into crystallization behavior and can be explored to rationally manipulate crystallization conditions for achieving desirable outcomes in batch or continuous crystallization processes.

This work aims to show the viability of applying video imaging techniques to the cooling crystallization of paracetamol in an oscillatory baffled crystallizer for the determination of the metastable zone width and crystal size distribution. From these data, the effects of supersaturation and mixing on metastable zone width and mean particle size are examined. Both sets of data are in good agreement with previous studies in a stirred tank and oscillatory baffled crystallizers. Finally, utilizing the Kubota's interpretation of metastable zone width, we demonstrated that the video imaging techniques are as sensitive to nucleation events as FBRM probes.